The present invention relates to therapeutic combinations comprising (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-pyrimidin-2-one (lamivudine) and BMS-200475, a cyclopentyl guanosine analogue. The present invention is also concerned with pharmaceutical compositions containing said combinations and their use in the treatment of HBV infections including infections with HBV mutants bearing resistance to nucleoside and/or non-nucleoside inhibitors of the replication of the hepatitis B virus.
Hepatitis B is a viral disease transmitted orally or parentally by contaminated material such as blood or blood products, contaminated needles, sexually, and vertically from infected or carrier mothers to their off-spring. In those areas of the world where the disease is common, vertical transmission at an early age results in a high proportion of infected individuals becoming chronic carriers of hepatitis B. An estimated 350 million people world-wide are chronically infected with hepatitis B and as many as 150 million may die from liver disease in the absence of intervention.
Currently, the only established approach to treatment of hepatitis B is repeated injections of interferon, which may be associated with unpleasant side effects, and produces a long lasting response in only one third or less of those treated. Interferon is an immune modulator designed to boost the disease fighting ability of the immune system.
Lamivudine has been reported to be effective against HBV in a two year study, showing that most patients showed substantially reduced levels of viral replication with 52% maintaining undetectable levels of virus thorough to the end of the second year.
The structure of BMS-200475 is as shown in formula (I); 
BMS-200475 has been reported to posses anti-HBV activity in vitro. Metabolic Studies on BMS-200475, a New Antiviral Compound with Activity Against Hepatitis B Virus. G Yasmanaka et al. 36th Interscience Conference on Antimicrobial Agents and Chemotherapy Sep. 15-18 1996, New Orleans, La. Oral BMS-200475 has also proved effective against Hepatitis B virus in woodchucks. Safety and pharmacokinetics of BMS-200475 have been studied in both single dose and 14-day multiple dose studies. Abstract 01 DeHertogh D, et al. Second International Conference on Therapies for Viral Hepatitis Kona, Big Island, Hi., Dec. 15-19, 1997.
The use of combinations of the invention may give rise to equivalent antiviral effect with reduced toxicity, or an increase in drug efficacy because synergy between compounds occurs. Lower overall drug doses will also possibly reduce the frequency of occurrence of drug resistant variants of HBV.
We have now found that lamivudine exhibits unexpected advantages when used in combination with BMS-200475. In particular the combinations shows a statistically significant synergistic anti-HBV effect. It is a feature of this invention that the use of this drug combination will provide synergistic antiviral effects, more complete viral suppression, viral suppression over longer periods, limit the emergence of drug resistant HBV mutants and allow better management of drug related toxicites. The use of these drug combinations may also result in a decrease of the number of, for example, tablets administered a day, therefore may increase patient compliance.
As will be appreciated by those skilled in the art, references herein to treatment extend to prophylaxis as well as to the treatment of established infections and symptoms.
Pharmaceutically acceptable salts of lamivudine, and BMS-200475 include those derived from pharmaceutically acceptable inorganic and organic acids. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene- p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids. Other acids such as oxalic acid, while not in themselves pharmaceutically acceptable may be useful in the preparation of salts useful as intermediates in obtaining compounds of the invention and their pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium), ammonium and NR4+ (where R is C1-4 alkyl) salts.
Preferred esters of lamivudine and BMS-200475 are independently selected from the following group: (1) carboxylic acid esters in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, n-propyl, t-butyl, or n-butyl), cycloalkyl, alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, C1-4 alkyl, or C1-4 alkoxy), or amino; (2) sulphonate esters, such as alkyl- or aralkylsulphonyl (for example, methanesulphonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); and (4) phosphonate esters. In such esters, unless otherwise specified, any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms. Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group. Any reference to any of the above compounds also includes a reference to a physiologically acceptable salt thereof.
Particularly preferred esters are the mono-, di-, and triphosphate esters of lamivudine and BMS-200475 (both of which may be optionally blocked), or any other compound which upon administration to a human subject is capable of providing (directly or indirectly) said mono-, di-, or triphosphate ester.
Thus according to one aspect, the present invention provides a combination comprising (2R,cis)-4-amino-1 -(2-hydroxymethyl-1,3-oxathiolan-5-yl)-pyrimidin-2-one or a pharmaceutically acceptable derivative thereof and BMS-200475 or a pharmaceutically acceptable derivative thereof.
Combinations as described above may herein after be referred to as combinations according to the invention.
As used herein xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d includes any pharmaceutically acceptable salt, ester or salt of such ester, of lamivudine, BMS-200475 or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) such a compound or an antivirally active metabolite or residue thereof.
The present invention further provides combinations according to the invention for use in therapy, particularly in the treatment of an HBV infection including infections resistant to nucleoside and/or non-nucleoside inhibitors of the replication of the hepatitis B virus.
According to another aspect, the present invention provides a method for the treatment of a mammal, including a human, suffering from an HBV infection comprising administration of a therapeutically effective amount of a combination according to the invention.
It will be appreciated that the compounds of the combination may be administered simultaneously, either in the same or different pharmaceutical composition, or sequentially. If there is sequential administration, the delay in administering the second active ingredient should not be such as to lose the benefit of a synergistic therapeutic effect of the combination of the active ingredients. It will also be understood that lamivudine and BMS-200475, or the pharmaceutically acceptable derivatives thereof whether presented simultaneously or sequentially, may be administered individually or in any combination thereof. Lamivudine and BMS-200475 are preferably administered simultaneously or sequentially in separate pharmaceutical formulations, most preferably simultaneously.
Preferably the combination according to the invention is administered as a single combined formulation.
The present invention also provides the use of lamivudine in the manufacture of a medicament for administration simultaneously or sequentially with BMS-200475 for the treatment of HBV infections. It will be appreciated that lamivudine or BMS-200475 may be used in the manufacture of the above medicament.
A further aspect of the invention is a combination according to the invention wherein the lamivudine and BMS-200475 are present in a synergistic ratio.
The synergistic effects of the combination of lamivudine and BMS-200475 or pharmaceutically acceptable derivatives thereof are seen over a ratio, for example, of 200:1 to 2:1 (by weight), preferably 100:1 to 10:1 (by weight).
Conveniently each compound will be employed in the combination in an amount at which it exhibits anti-HBV activity when used alone.
The amount of a combination of lamivudine and BMS-200475 required to be effective as an anti-HBV agent will, of course, vary and is ultimately at the discretion of the medical practitioner. The factors to be considered include the route of administration and nature of the formulation, the animal""s body weight, age and general condition and the nature and severity of the disease to be treated.
In general for lamivudine a suitable daily dose will be in the range of from about 0.1 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 0.5 to 20 mg per kilogram body weight per day, most preferably in the range of 0.5 to 2 mg per kilogram body weight per day.
The compound is conveniently administered at a level of about 100 mg per day.
For BMS-200475, a suitable daily dose will be in the range of from about 0.02 to about 1 mg per kilogram body weight of the recipient per day, preferably in the range of 0.02 to 0.1 mg per kilogram body weight per day, most preferably in the range of 0.01 to 0.05 mg per kilogram body weight per day.
Unless otherwise indicated all weights of active ingredients are calculated in terms of the drug per se. In the case of a pharmaceutically acceptable derivatives of lamivudine and BSM-200475 or a solvate thereof the figures would be increased proportionately. The desired dose is preferably presented as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing from 1 to 1500 mg, preferably from 5 to 1000 mg, most preferably from 5 to 500 mg of active ingredient per unit dosage form. Alternatively, if the condition of the recipient so requires, the dose may be administered as a continuous infusion.
The components of the combination which may be referred to as active ingredients may be administered for therapy to an animal e.g. a mammal including a human in a conventional manner.
While it is possible for the active ingredients of the combination to be administered as the raw chemical it is preferable to present them as a pharmaceutical composition. Pharmaceutical compositions according to the present invention comprise a combination according to the invention in association with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formula and not deleterious to the recipient thereof. When the individual components of the combination are administered separately they are generally each presented as a pharmaceutical composition. The references hereinafter to compositions refer unless otherwise stated to compositions containing either the combination or a component thereof.
A combination of lamivudine and BMS-200475 or pharmaceutically acceptable derivatives thereof may conveniently be presented as a pharmaceutical composition with one or more pharmaceutically acceptable carrier thereof in a unitary dosage form. A convenient unitary dosage formulation contains the active ingredients in amounts of from 1 mg to 2 g each, for example, 2 mg to 200 mg such as 25 to 150 mg of lamivudine and 2.5 to 20 mg of BMS-200475.
Pharmaceutical compositions may also be prescribed to the patient in xe2x80x9cpatient packsxe2x80x9d containing the whole course of treatment in a single package, usually a blister pack. Patient packs have an advantage over traditional prescriptions, where a pharmacists divides a patients supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in traditional prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the physicians instructions.
It will be understood that the administration of the combination of the invention by means of a single patient pack, or patients packs of each composition, within a package insert diverting the patient to the correct use of the invention is a desirable additional feature of this invention.
According to a further aspect of the invention there is provided a patient pack comprising at least one active ingredient of the combination according to the invention and an information insert containing directions on the use of the combination of the invention.
According to another aspect the invention provides a double pack comprising in association for separate administration lamivudine and BMS-200475 or pharmaceutically acceptable derivatives thereof.
Compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods represent a further feature of the present invention and include the step of bringing into association the active ingredients with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, caplets, cachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent. Moulded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredients therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
Preferably the combinations according to the invention are administered orally. Compositions suitable for topical administration in the mouth include lozenges comprising the active ingredients in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier. Compositions for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
Topical administration may also be by means of a transdermal iontophoretic device.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by admixture of the active combination with the softened or melted carrier(s) followed by chilling and shaping in moulds.
Formulations suitable for parenteral administration include aqueous and nonaqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents; and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Preferred unit dosage formulations are those containing a daily dose or daily subdose of the active ingredients, as herein before recited, or an appropriate fraction thereof.
It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavouring agents.
The compounds of the combination of the present invention may be obtained in a conventional manner.
Methods for the preparation of lamivudine are described in International Patent Applications Numbers. WO91/17159, and WO 95/29174 incorporated herein by reference.
Methods for the preparation of BMS-200475 are described in European Patent No. 0 481 754 incorporated herein by reference.
The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way. xe2x80x9cActive ingredientxe2x80x9d denotes lamivudine or BMS-200475 or multiples thereof or a physiologically functional derivative of any of the aforementioned compounds.